US20090118330A1 - Diurea derivatives - Google Patents

Diurea derivatives Download PDF

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US20090118330A1
US20090118330A1 US10/585,054 US58505405A US2009118330A1 US 20090118330 A1 US20090118330 A1 US 20090118330A1 US 58505405 A US58505405 A US 58505405A US 2009118330 A1 US2009118330 A1 US 2009118330A1
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ethyl
phenyl
trifluoromethyl
urea
ureido
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Aina Lisbeth Abramo
Lars Olof Goran Pettersson
Kerstin Ingalill Andersson
Asa Anette Sundstedt
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Active Biotech AB
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Active Biotech AB
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    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D213/72—Nitrogen atoms
    • C07D213/75—Amino or imino radicals, acylated by carboxylic or carbonic acids, or by sulfur or nitrogen analogues thereof, e.g. carbamates
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    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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    • A61P25/00—Drugs for disorders of the nervous system
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    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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    • A61P3/00—Drugs for disorders of the metabolism
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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    • A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
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    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
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    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A61P37/02—Immunomodulators
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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    • A61P37/00—Drugs for immunological or allergic disorders
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    • A61P37/04—Immunostimulants
    • A—HUMAN NECESSITIES
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    • A61P37/06—Immunosuppressants, e.g. drugs for graft rejection
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
    • C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
    • C07D215/16—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D215/38—Nitrogen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
    • C07D295/04—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms
    • C07D295/12—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly or doubly bound nitrogen atoms
    • C07D295/125—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly or doubly bound nitrogen atoms with the ring nitrogen atoms and the substituent nitrogen atoms attached to the same carbon chain, which is not interrupted by carbocyclic rings
    • C07D295/13—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly or doubly bound nitrogen atoms with the ring nitrogen atoms and the substituent nitrogen atoms attached to the same carbon chain, which is not interrupted by carbocyclic rings to an acyclic saturated chain

Definitions

  • the present invention relates to diurea derivatives that block intracellular signal transduction and inhibit interleukin-2 (IL-2) production, to methods for their preparation, to compositions containing them and to methods and use for clinical treatment of autoimmune diseases, inflammatory diseases, organ transplant rejection and other disorders associated with IL-2 mediated immune response as well as conditions of malignant neoplasia. Because of their selective immunomodulating properties, these compounds and pharmaceutical compositions of this invention are particularly useful for preventing and treating acute or chronic inflammation, autoimmune disease (rheumatoid arthritis, multiple sclerosis, type-1 diabetes, inflammatory bowel disease, psoriasis), graft versus host disease (and other forms of organ or bone marrow transplant rejection) and malignant neoplastic disease. More particularly, the present invention relates to novel diurea derivatives suitable for the treatment of, for example, rheumatoid arthritis and graft versus host disease.
  • IL-2 interleukin-2
  • T lymphocytes play a central role in the immune response, both as direct effector cells and as regulatory cells that modulate the functions of numerous other cell types, primarily those that participate in the body's defence mechanisms. This regulatory function is provided either through direct cell-cell contact or via the secretion of various cytokines. Thus the proper function of T-cells is essential for the maintenance of normal homeostasis within and outside the immune system. Conversely, abnormalities in their function can lead to immunological diseases, e.g. autoimmunity, allergies and immunodeficiences. Indeed, activation of T-cells is often the initiating event in many inflammatory and autoimmune diseases.
  • T cells of the T helper 1 (Th1) type play a pivotal role in orchestrating inflammatory immune responses.
  • Th1 cells produce pro-inflammatory cytokines, which are commonly associated with cell-mediated immunity and induction of organ-specific autoimmune diseases (Abbas et al. 1996).
  • the cytokine IL-2 is a principal regulator of Th1 activity (Waldmann et al. 2001).
  • IL-2 is an autocrine growth factor that plays an essential role in the regulation of T-cell activation and proliferation.
  • autoimmune diseases such as rheumatoid arthritis, multiple sclerosis, type-1 diabetes, inflammatory bowel disease, and psoriasis occur.
  • IL-2 graft-versus-host disease
  • IL-2 dysregulation of other pro-inflammatory Th1 cytokines (including TNF- ⁇ and IFN- ⁇ ) has also been implicated in the pathogenesis of inflammatory and autoimmune diseases (Sacca et al. 1997).
  • Clinical studies have shown that interference with IL-2 activity effectively suppresses immune response in vivo (Waldmann et al. 1993). Accordingly, agents that inhibit IL-2 production are therapeutically useful for selectively suppressing immune response in a patient in need of such immunosuppression.
  • a common immunopathological hallmark of many autoimmune inflammatory diseases is a T-cell invasion and accumulation at the inflamed tissue.
  • One mechanism implicated in this process is the failure to remove autoreactive T-cells due to defects in activation-induced cell death (Eguchi et al. 2001), suggesting that lack of apoptosis is involved in the pathogenesis of autoimmunity.
  • approaches that attempt to correct underlying immunoregulatory defects in autoimmune disease could include inventions aimed at inhibiting cytokines (such as IL-2) and/or deleting autoreactive Th1 cells. Inappropriate survival of lymphocytes is also associated with an increased occurrence of lymphoma (Bleesing et al. 2003).
  • tumour formation an important aspect of tumour development in general is the suppression of apoptosis, and human tumours seem to utilise several different mechanisms to evade cell suicide (White et al. 2001). Therefore, strategies to circumvent anti-apoptotic mechanisms and to activate apoptosis in tumour cells would suppress tumour formation.
  • IL-2R IL-2/IL-2 receptor
  • This approach would block the proliferative activity of IL-2/IL-2R binding but fails to inhibit other pro-inflammatory cytokines.
  • the use of antibodies directed against IL-2Rx has been described. However, these antibodies are not orally bioavailable. Inhibition of IL-2 action can also be achieved by the use of more general immunosuppressive drugs, such as glucocorticoids, cyclosporine, azathioprione, or mycophenolate mofetil. These compounds are relatively non-selective and suffer from dose-limiting side effects. Accordingly, a need exists for compounds that effectively inhibit IL-2 production for preventing and treating immune disorders.
  • Diurea derivatives can also be found in the CA Chemcat database. No pharmacological activities have been ascribed to these compounds.
  • the compounds of this invention inhibit production of IL-2 and other pro-inflammatory cytokines by T-cells by inhibiting intracellular signalling.
  • This inhibition of IL-2 is therapeutically useful for selectively suppressing immune function.
  • Compounds also promote the induction of apoptosis in activated T-cells.
  • the result of such selectively suppressed immunity includes reduced cell proliferation of peripheral blood lymphocytes and cellular immune response without serious toxicity or undesired side effects.
  • the inhibition of IL-2 production and/or induction of apoptosis in activated T-cells are attractive means for preventing and treating a variety of immune disorders, including inflammatory diseases, autoimmune diseases, organ and bone marrow trans-plant rejection and other disorders associated with IL-2 mediated immune response and defective cell regulation.
  • the compounds may be used to prevent or treat acute or chronic inflammation, rheumatoid arthritis, multiple sclerosis, type-1 diabetes, inflammatory bowel disease, psoriasis, graft versus host disease (and other forms of organ or bone marrow transplant rejection) and malignant neoplastic disease.
  • FIG. 1 The effect (% of non-treated stimulated cells) of Compound A on PMA/Ionomycin stimulated IL-2 production in human T-cells. The curve is from a typical experiment.
  • the objective problem of the present invention is to provide compounds which by virtue of their pharmacological profile, with high potency in experimental models and low level of side-effects, are considered to be of value in the treatment of disease associated with pathologic inflammation, autoimmunity or other pathologic cell regulation. Included in the invention is also the use of the compounds for the preparation of a medicament for the inhibition of IL-2 production. These compounds also inhibit the production of other pro-inflammatory cytokines such as tumour necrosis factor- ⁇ (TNF- ⁇ ), interleukin-6 (IL-6) and interferon- ⁇ (IFN- ⁇ ) and promote apoptosis (activation-induced cell death).
  • TNF- ⁇ tumour necrosis factor- ⁇
  • IL-6 interleukin-6
  • IFN- ⁇ interferon- ⁇
  • this invention provides preparation of a medicament for the inhibition of IL-2 production, a method of treating diseases in which the disease pathology may be therapeutically modified by inhibiting IL-2 production and T-cell activation.
  • diseases are inflammatory and autoimmune diseases, organ transplant rejection, as well as malignant neoplastic diseases.
  • the compounds may be used to prevent or treat acute or chronic inflammation, rheumatoid arthritis, multiple sclerosis, type-1 diabetes, inflammatory bowel disease, psoriasis, graft versus host disease (and other forms of organ or bone marrow transplant rejection) and malignant neoplastic disease.
  • the present invention relates to novel diurea derivatives-suitable for the treatment of, for example, rheumatoid arthritis and graft versus host disease.
  • the present invention relates to a compound of the general formula I
  • A is Ph-Y (1-3) or Ar—X (0-2) ;
  • R1 is selected from dimethylamino, diethylamino, diisopropylamino, pyrrolidino, piperidino, and 4-methyl-piperazino, and unsubstituted or substituted phenyl with substitutents selected from fluoro, chloro, bromo and methyl;
  • Ar is selected from phenyl, 1-naphtyl, 2-naphtyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, 6-quinolinyl, and 5-pyrimidinyl;
  • X (0-2) represents 0 to 2 substituents selected from C1-C6 branched or unbranched alkyls, C1-C6 branched or unbranched alkyloxy, C1-C6 branched or unbranched acyls, fluoro, chloro, bromo, trifluoromethyl, dimethylamino, diethylamino and trifluoromethoxy;
  • Y (1-3) represents 1 to 3 substituents selected from fluoro, chloro, bromo, dimethylamino, diethylamino, trifluoromethyl, and methoxy;
  • Z is O or S
  • n 1-3;
  • n is 1-4, preferably 2-4 or pharmaceutically acceptable salts of the compounds of the general formula I.
  • R1 is selected from dimethylamino, diethylamino, diisopropylamino, pyrrolidino, piperidino, and 4-methyl-piperazino;
  • Y (1-3) represents 1 to 3 substituents selected from fluoro, chloro, bromo, dimethylamino, diethylamino, trifluoromethyl, and methoxy;
  • Z is O or S
  • n 1-3;
  • n is 2-4, or pharmaceutically acceptable salts of the compounds of the general formula Ia.
  • R1 is selected from dimethylamino, diethylamino, diisopropylamino, pyrrolidino, piperidino, and 4-methyl-piperazino;
  • Ar is selected from phenyl, 1-naphtyl, 2-naphtyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, 6-quinolinyl, and 5-pyrimidinyl;
  • X (0-2) represents 0 to 2 substituents selected from C1-C6 branched or unbranched alkyls, C1-C6 branched or unbranched alkyloxy, C1-C6 branched or unbranched acyls, fluoro, chloro, bromo, trifluoromethyl, dimethylamino, diethylamino and trifluoromethoxy;
  • Y (1-3) represents 1 to 3 substituents selected from fluoro, chloro, bromo, dimethylamino, diethylamino, trifluoromethyl, and methoxy;
  • Z is O or S
  • n 1-3;
  • n is 2-4, or pharmaceutically acceptable salts of the compounds of the general formula Ib.
  • R1 is selected from dimethylamino, diethylamino, diisopropylamino, pyrrolidino, piperidino, 4-methyl-piperazino;
  • n 2 and 3;
  • n is selected from 1 and 2;
  • Y (1-3) is one substituent selected from fluoro, chloro, bromo, trifluoromethyl, dimethylamino and diethylamino.
  • Ar is selected from phenyl, 2-naphtyl and 4-pyridyl,
  • n 2 and 3;
  • Y (1-3) is one of the substituents selected from fluoro, chloro, bromo, and trifluoromethyl.
  • the present invention relates to a compound as described above for use as a medicament.
  • the present invention relates to the use of a compound as described above for the manufacturing of a medicament for the treatment of immune disorders which benefit from inhibition of production of IL-2 and other pro-inflammatory cytokines and/or induction of apoptosis in activated T-cells.
  • the immune disorders are chosen from the group comprising inflammatory diseases, autoimmune diseases, organ and bone marrow trans-plant rejection and other disorders associated with pro-inflammatory cytokines, especially IL-2, mediated immune response and defective cell regulation.
  • the immune disorders are chosen from the group comprising acute or chronic inflammation, rheumatoid arthritis, multiple sclerosis, type-1 diabetes, inflammatory bowel disease, psoriasis, graft versus host disease and malignant neoplastic disease.
  • the present invention relates to a pharmaceutical composition
  • a pharmaceutical composition comprising a compound as described above, admixed with one or more pharmaceutically acceptable excipients or carriers.
  • the excipients are chosen from the group comprising filling agents, lubricants, flavours, colourings, sweetening, buffers, acidifying agents, diluents and preservatives.
  • the pharmaceutical composition is administered orally, intramuscularly, intravenously, intraperitoneally or subcutaneously, via implants, rectally, intranasally, transdermally, topically, or parenterally.
  • the present invention relates to a method of treatment comprising administration of a pharmaeutically effective amount of compound or a pharmaceutical composition as described above to a subject suffering from an immune disorder which benefit from inhibition of production of IL-2 and other pro-inflammatory cytokines and/or induction of apoptosis in autoreactive T-cells.
  • the immune disorder is chosen from the group comprising inflammatory diseases, autoimmune diseases, organ and bone marrow transplant rejection and other disorders associated with pro-inflammatory cytokines, especially IL-2, mediated immune response and defective cell regulation.
  • the immune disorders are chosen from the group comprising acute or chronic inflammation, rheumatoid arthritis, multiple sclerosis, type-1 diabetes, inflammatory bowel disease, psoriasis, graft versus host disease and malignant neoplastic disease.
  • the compounds of general formula (I) may be prepared by methods known in the literature and the following methods.
  • the compounds of general formula (I) may be prepared by methods well known in the art. General methods of preparation are shown in Scheme A (the “symmetrical” diurea derivatives) and Scheme B (the “asymmetrical” diurea derivatives).
  • a “symmetric” diurea derivative of formula (Ia) may be prepared by conventional methods, for example, by reacting the isocyanate derivative (II) with the diamine dervative (III) in an inert solvent like dichloromethane (Scheme A).
  • the diamine (III) may first be protected by conventional methods, like t-BOC (intermediate (V), or it can be used in excess to reduce diacylation, to produce an “asymmetric” diurea derivative (Ib) (Scheme B).
  • a microwave-assisted reaction were carried out in capped vials using a microwave oven with temperature and pressure control.
  • a solution of quinoline-6-carbonyl azide (29.9 mg, 0.15 mmol) in 1.5 mL CH 2 Cl 2 was heated at 110° C. for 15 minutes.
  • 1-(2-Amino-ethyl)-1-(2-pyrrolidin-1-yl-ethyl)-3-(4-trifluoromethyl-phenyl)-urea 52 mg 0.15 mmol
  • the product was purified by flash silica gel chromatography using, MeOH: Et 3 N 100:1 as the eluent. Concentration in vacuum of the product-rich fractions provided the title compound (45 mg, 55%).
  • the compounds of formula (I) were assayed for inhibition of IL-2 production.
  • the compounds to be evaluated were dissolved in DMSO and the dilution series of the compounds were prepared in DMSO.
  • the series were further diluted in cell culture medium (RPMI 1640 with ultraglutamine, 10% foetal calf serum (FCS)) to obtain a final assay concentration of DMSO of 0.1% in 200 ⁇ l total volume.
  • the compounds were plated (2 ⁇ l/well) on opaque white assay plates together with controls.
  • PBMC Peripheral blood mononuclear cells
  • T-cells CD4+
  • MCS magnetic cell sorting
  • the cells were resuspended at 1 ⁇ 10 6 cells/ml in cell culture medium (RPMI 1640 with ultraglutamine, 10% FCS, 10 mM hepes, 1 mM sodium pyruvate and 0.1 mg/ml gentamicin).
  • the cells (1 ⁇ 10 5 /well) were added to the assay plates containing the diluted compounds and pre-incubated for 30 min at 37° C. in a humidified atmosphere of 5% carbon dioxide.
  • the cells were stimulated with 10 ng/ml phorbol myristate acetate (PMA) and 250 ng/ml ionomycin and the plates were incubated for 4 hours at 37° C. in a humidified atmosphere of 5% carbon dioxide.
  • Approximately 100 ⁇ l of the supernatants were removed and transferred to a separate microtiter plate and the remaining cells were lysed (Nucleotide Releasing Reagent, ViaLightTM, Cambrex). All the plates were kept at ⁇ 20° C. pending analysis.
  • IL-2 Human interleukin-2
  • OptEIATM Human interleukin-2
  • Viability was assessed by measuring adenosine triphosphate (ATP) content by adding luciferase (ATP monitoring reagent, ViaLightTM, Cambrex) to the lysed cells and measuring luminescence, all according to the manufacturer's specifications.
  • ATP adenosine triphosphate
  • peripheral blood mononuclear cells By similar methods using peripheral blood mononuclear cells, appropriate stimuli, and commercially available ELISA kits, for a particular cytokine, inhibition of IL-6, TNF- ⁇ and IFN- ⁇ were demonstrated.
  • the induction of apoptosis can be observed by measuring Annexin V-binding to cells (Van Engeland et al. 1998).
  • Primary human CD4 + T cells were isolated from peripheral blood from healthy volunteers as described above. Cells were cultured immediately after purification at a density of 2 ⁇ 10 6 cells/ml in RPMI 1640 medium supplemented with 10% FCS, Gentamycin (100 ⁇ g/ml), Hepes (10 mM) and Sodium Pyruvate (1 mM). Cells were stained with annexin V-FITC and propidium iodide by using the ApoAlert Annexin V-FITC Apoptosis Kit (Clontech) according to manufacturer's instructions. Flow cytometry analysis was performed using a FACScan (Becton Dickinson).
  • induction of apoptosis can be demonstrated measuring cleavage of the caspase-substrate PARP (poly(ADP-ribose)polymerase) (Tang et al. 1996).
  • Cell lysates were prepared by lysing 2 ⁇ 10 6 PBS-washed cells in 50 ⁇ l buffer containing 20 mM Tris-HCl, pH 7.7, 250 mM NaCl, 3 mM EDTA, 3 mM EGTA 0.5% NP-40 supplemented with 1 mM p-nitrophenyl phosphate (PNPP), 10 mM ⁇ -glycerophosphate, 100 ⁇ M Na-vanadate and 1 mM phenylmethansulfonyl fluoride (PMSF).
  • PNPP p-nitrophenyl phosphate
  • PMSF phenylmethansulfonyl fluoride
  • the protein concentrations were determined by using Bio-Rads protein assay and thereafter equal amounts of protein was loaded onto precasted NuPAGETM Tris-Bis gels (Novex). After electrophoresis, the proteins were transferred to nitrocellulose membrane and probed with a polyclonal rabbit antibody directed against PARP (Roche). Proteins were visualised after incubations with a horseradish peroxidase-conjugated secondary anti-body and ECL reagents (Amersham Bioscience).
  • DNA fragmentation was extracted using Suicide-Track DNA Ladder Isolation Kit (Oncogene Research Products) according to manufacturer's instructions. DNA fragmentation was visualised on 1.5% agarose gels in the presence of ethidium bromide.
  • Compound A 1-(2-diethylaminoethyl)-3-(3-trifluoromethyl-phenyl)-1- ⁇ 2-[3-(3-trifluoromethyl-phenyl)-ureido]-ethyl ⁇ -urea, hydrochloride hereinafter called Compound A.
  • the effect of Compound A on PMA/Ionomycin stimulated IL-2 production in human T-cells was determined ( FIG. 1 ).
  • Compound A The effect of Compound A on PMA/Ionomycin stimulated IL-6, TNF- ⁇ and IFN- ⁇ production in human peripheral blood mononuclear cells was determined.
  • Effective quantities of the compounds of formula (I) are preferably administered to a patient in need of such treatment according to usual routes of administration and formulated in usual pharmaceutical compositions comprising an effective amount of the active ingredient and one or more suitable pharmaceutically acceptable excipients or carriers.
  • Such compositions may take a variety of forms, e.g. solutions, suspensions, emulsions, tablets, capsules, and powders prepared for oral administration, aerosols for inhalation, sterile solutions for parental administration, suppositories for rectal administration or suitable topical formulations.
  • Conventional procedures for the selection and preparation of suitable pharmaceutical formulations are described, for example, in “Pharmaceuticals—The Science of Dosage Form Design”, M. B. Aulton, Churchill Livingstone, (1988).
  • a suitable daily dose for use in the treatment of rheumatoid arthritis is contemplated to vary between 0.0005 mg/kg to about 10 mg/kg body weight, in particular between 0.005 mg/kg to 1 mg/kg body weight, depending upon the specific condition to be treated, the age and weight of the specific patient, and the specific patient's response to the medication.
  • the exact individual dosage, as well as the daily dosage, will be determined according to standard medical principles under the direction of a physician.
  • the pharmaceutical composition may also contain additional therapeutically useful substances other than a compound of formula (I).

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US10/585,054 2004-02-04 2005-01-19 Diurea derivatives Abandoned US20090118330A1 (en)

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US54123104P 2004-02-04 2004-02-04
SE0400213A SE0400213D0 (sv) 2004-02-04 2004-02-04 Diurea Derivatives
SE0400213-5 2004-02-04
PCT/SE2005/000054 WO2005074919A1 (fr) 2004-02-04 2005-01-19 Derives de diuree
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Cited By (1)

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Publication number Priority date Publication date Assignee Title
US10932942B2 (en) 2015-02-02 2021-03-02 C.R. Bard, Inc. Drainage bag systems including at least one indicator element and methods of using the same

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Publication number Priority date Publication date Assignee Title
NZ583351A (en) * 2007-08-15 2012-05-25 Cytokinetics Inc Modulate smooth muscle myosin and/or non-muscle myosin
US20120264755A1 (en) * 2009-06-09 2012-10-18 TopoTarget Pyridinyl derivatives as inhibitors of enzyme nicotinamide phosphoribosyltransferase

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US2745874A (en) * 1953-06-18 1956-05-15 Geigy Ag J R Insecticidal derivatives of diphenyl urea
US5057539A (en) * 1987-11-24 1991-10-15 Ciba-Geigy Corporation Moth- and beetle-proofing agents

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CN1021819C (zh) * 1988-01-20 1993-08-18 山之内制药株式会社 作为药物有用的双脲衍生物的制备方法
WO1993016992A1 (fr) * 1992-02-20 1993-09-02 Merrell Dow Pharmaceuticals Inc. Derives d'acide sulfonique utilises dans le traitement de maladies virales
AU9005398A (en) * 1997-09-11 1999-03-29 Yuhan Corporation Thiourea derivatives or non-toxic salts thereof for inhibitng ras-transformed cell growth
EP1085846A2 (fr) * 1998-06-08 2001-03-28 Advanced Medicine, Inc. Inhibiteurs multiliaison de proteine triglyceride transferase microsomique
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US2745874A (en) * 1953-06-18 1956-05-15 Geigy Ag J R Insecticidal derivatives of diphenyl urea
US5057539A (en) * 1987-11-24 1991-10-15 Ciba-Geigy Corporation Moth- and beetle-proofing agents

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US10932942B2 (en) 2015-02-02 2021-03-02 C.R. Bard, Inc. Drainage bag systems including at least one indicator element and methods of using the same
US11045345B2 (en) 2015-02-02 2021-06-29 C.R. Bard, Inc. Drainage bag systems including at least one indicator element and methods of using the same

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CA2551566A1 (fr) 2005-08-18
WO2005074919A1 (fr) 2005-08-18

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